- Structural damage of white matter (WM) and grey matter (GM),
- Inflammatory processes (within or outside the central nervous system, CNS),
- Maladaptive network recruitment due to distributed lesions or inflammation,
- Metacognition (self-monitoring) of interoception of dyshomeostatic state.
Structural brain damage:
The white matter and the grey matter results in the mechanism of the fatigue.
White matter lesions:
Active dependent conduction block might contribute to fatigability. Fampridine is thought to improve the conduction of the action potentials in demyelinated nerves by blocking voltage gated potassium channels.
Two different degenerative mechanisms in cortex, that is, inflammation-induced oxidative injury of neurons and retrograde neurodegeneration due to axonal transection. In subcortical regions, frequent sites of GM lesions include the thalamus, basal ganglia, amygdala, substantia nigra and hypothalamus.
Orexin a neuropeptide of basic importance of arousal and vigilance , in a patient with the narcolepsy a disease which dramatically reduces the vigilance and autoimmunological reactions against orexin producing neurons strongly decreases orexin levels. Lees production of orexin might results in fatigueness of individuals.transmitetr suppl
Lesions of dopaminergic, serotonergic or noradrenergic nuclei in the brainstem and the consequent reduction of monoaminergic transmitter supply to cortex and basal ganglia could explain the reduction in motivation. Grey matter lesions in hypothalamus or brainstem nuclei could disturb the hypothalamus pituitary adrenal axis and descending neural control of the autonomic nervous system leading to persistent endocrine and autonomic disturbances.
Immunological and Inflammatory processes:
Peripheral immunological and inflammatory processes are likely to play a central role for fatigue.
Peripheral immunological and inflammatory processes are likely to play a central role for fatigue, in general, and in the specific context of MS. This is illustrated by ‘sickness behaviour’, a syndrome of fatigue, social withdrawal and lowered mood during common infections that trigger the production of proinflammatory cytokines. Furthermore, fatigue can be induced by immunomodulatory drugs like interferon-α or vaccinations that trigger production of proinflammatory cytokines.
Maladaptive network recruitment during task performance:
Regulate neuronal gain and excitability via slow afterhyperpolarisation currents mediated by calcium-dependent potassium channels second, they alter both short-term and long-term synaptic plasticity by modulating NMDA receptors. Rapid functional reorganisation of cortical networks in response to manipulations of neuromodulatory transmitters was demonstrated in human and animal studies, and it is conceivable that similar effects could arise from brainstem lesions in MS or through effects of inflammation on monoamine synthesis.
Metacognitive perspective on fatigue:
Dyshomeostatic state including immunological, metabolic, endocrine, cardiovascular, hepatic and renal diseases.
The diminished sensory attenuation during the execution of movements lead to proprioceptive prediction errors, requiring the brain to conclude that movements require more effort than predicted.